The present invention relates to novel quinoline derivatives, to intermediates used in their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are agonists of serotonin 7 (5HT7) receptors. They are useful in treating CNS disorders, including depression and disorders that can be treated by modulating circadian rhythms. Examples of such disorders and conditions are seasonal affective disorder, bipolar disorder, jet lag, sleep disorders such as circadian sleep rhythm disorder, sleep deprivation, REM sleep disorders, hypersomnia, parasomnias, sleep-wake cycle disorders, narcolepsy, sleep disorders associated with blindness, sleep disorders associated with obesity, and sleep disorders associated with shift work or irregular work schedules; nocturnal enuresis, and restless leg syndrome.
Serotonin 7 receptors are present in the suprachiasmatic nucleus (SCN), the brain region that contains the biological clocks, and their activation leads to a resetting of the clocks as a function of dose and timing of treatment. Such a mechanistic link is evident in numerous paradigms—in in vitro electrophysiological studies of SCN neuronal activity, and in light induced changes in wheel running behavior and nighttime melatonin suppression—in each case activation of 5HT7 receptors having the potential to modulate both clock function and the clock resetting ability of light. Full agonists and partial agonists of the 5HT7 receptor therefore offer a wide range of clinically useful therapeutics.
Glennon's article “Serotonin Receptors: Clinical Implications”, Neuroscience and Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease.